Rac1 (Ras-related C3 botulinum toxin substrate 1) serves as a molecular switch by the hydrolysis of GTP to GDP. Because of the slow rate of hydrolysis of GTP and dissociation of GDP, Rac1 requires guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) for its regulation. Despite being considered undruggable because of its small size and shallow surface, the binding of GAPs and GEFs suggests the existence of transient binding pockets on Rac1. Using molecular dynamics simulations, we identified four such pockets: two serve as GEF binding sites, a third interacts with DHR domain-containing GEFs from the DOCK family, and the fourth binds the engulfment and cell motility 1 (ELMO1) protein. To adequately sample the open states of these pockets, we used cosolvent molecular probes for MD simulations. Principal component analysis of the cosolvent MD simulations helped us to understand significant domain movements. We attempted to use this information to understand how these transient pockets open and close. Our work reveals transient pockets that GEF proteins could use, leading to new avenues for drug design.
Soybean serves as a primary global source of high-quality protein and oil, and improving its yield and quality is critical for global food security. Despite advances in gene editing and molecular breeding, the regulatory mechanisms underlying leaf senescence remain poorly understood, limiting yield gains in soybean. Building on our previous identification of SNAP1/2/3/4-a cluster of NAC transcription factors regulating nodule senescence-we reported their pivotal role in modulating aboveground agronomic traits. The knockout mutants of SNAP1/2/3/4 exhibited delayed leaf senescence and prolonged maturation period. These changes led to concurrent improvements in grain yield, seed size, and oil content. Our study reveals a dual regulatory function of SNAP1/2/3/4 in both nodule and leaf senescence and uncovers a molecular target to coordinately enhance soybean yield and quality by fine-tuning of developmental timing.
Operative orthopaedic care in resource-constrained systems is frequently limited by theatre time, staffing, peri-operative support, implants, instruments and bed availability. In the absence of an explicit prioritisation framework, decisions about patients awaiting surgery may vary between clinicians and institutions. This modified Delphi study aimed to establish consensus on factors that should structure prioritisation of operative orthopaedic care in South African public hospitals. A three-round modified Delphi study was conducted among South African public-sector orthopaedic clinicians. Round 1 used open-ended responses to generate candidate prioritisation factors. Round 2 used a structured 1-9 importance scale to rate patient-specific factors, injury-specific factors, red-flag conditions and potential tie-breakers. Round 3 verified operational definitions, anchor levels and red-flag handling. The scope was confined a priori to admitted patients with stable, isolated orthopaedic injuries; polytrauma, spinal cord injuries and unstable vertebral fractures were excluded because they require individualised, time-critical prioritisation through established emergency pathways. Inclusion consensus was defined as a median score of at least 4 with at least 75% of respondents rating the factor 4-9. Strong inclusion consensus required a median score of at least 7 with at least 75% rating the factor 7-9. Binary consensus required at least 75% agreement. Following exclusion, 65, 55 and 63 responses were analysed in Rounds 1, 2 and 3, respectively. Six patient-specific factors reached inclusion consensus: age, diabetes mellitus, severe cardiac or respiratory disease, premorbid functional status, physiological reserve and current psychosis or severe psychiatric instability. All six injury-specific factors reached inclusion consensus. Soft-tissue status, anatomical site and neurovascular status reached strong inclusion consensus; fracture type or pattern, injury energy and time already waited for surgery reached inclusion consensus. Acute compartment syndrome and threatened vascular status of the relevant limb reached consensus as automatic red-flag overrides. No proposed tie-breaker reached consensus. This study provides a consensus framework for factors influencing the prioritisation of patients awaiting operative orthopaedic care in a low- and middle-income country (LMIC) setting. The findings support a preliminary framework, rather than a validated scoring system. Prospective weighting, inter-rater reliability testing and outcome validation are required before implementation as a formal prioritisation tool.
To assess differences in risk factors for uterine cancer (UC) mortality, differences in five-year overall survival across clinical and demographic characteristics, and independent predictors of mortality among Black and White patients. Patients treated between January 1, 2002, and December 31, 2022, at a specialized urban cancer center in the northeastern United States. This study used a retrospective analysis of data from an internal registry. Differences in overall survival across age, race, education, area income, stage, grade, and histology were compared using Kaplan-Meier curves. Survival was compared across characteristics using pairwise log-rank tests, followed by a Cox proportional hazards regression model to identify predictors of mortality. Among 4,891 patients, 262 self-identified as African American or Black. Compared to non-Hispanic White patients, Black patients were more likely to experience risk factors for UC mortality. Kaplan-Meier curves suggested reduced survival in patients with fewer resources. In the adjusted model, older age, advanced disease, higher tumor grade, and not having graduated from high school were associated with a greater likelihood of mortality. Socioeconomic factors may contribute to racial disparities in UC survival. Earlier diagnosis and enhanced patient support may address modifiable risk factors for UC mortality.
Obligate biotrophic powdery mildew (PM) fungi strictly require living hosts to survive. To search for host factors or processes essential for PM pathogenesis, we conducted a tailored forward genetic screen with the immuno-compromised eds1-2/pad4-1/sid2-2 (eps) triple Arabidopsis mutant. This led to the identification of five allelic disruptive mutations in Mildew Locus O 2 (MLO2) that are responsible for the compromised-immunity-yet-poor infection (cipi) mutant phenotype upon challenge with an adapted PM isolate. Moreover, the eds1/pad4/sid2/mlo2/mlo6/mlo12 (eps3m) sextuple and the eds1/pad4/sid2/pen1/pen2/pen3/mlo2/mlo6/mlo12 (eps3p3m) nonuple mutants displayed near-complete immunity to adapted and non-adapted PM fungi without signs of defense activation, further strengthening the inference that these three clade V MLOs in Arabidopsis may be bona fide host susceptibility factors of PM fungi. Confocal imaging revealed focal accumulation of MLO2-GFP in the peri-penetration peg membranous space, which occurs before and may be required for haustorium differentiation. Ectopic leaf expression analyses of eight other MLOs belonging to different clades showed that only MLO7 can complement the loss of MLO2, MLO6, and MLO12. Results from domain-swapping analyses between MLO1 and MLO2 suggest a bipartite functional configuration for MLO2: its cytoplasmic C-terminus determines where and when MLO2 functions, while its N-terminal seven transmembrane domain-containing region executes the cellular function that is critical for PM pathogenesis. Genetic studies further demonstrated that, unlike MLO7 in synergids, focal accumulation of MLO2 does not depend on FERONIA (FER) and its five paralogs. Together, these findings define clade V MLOs as host factors co-opted by obligate biotrophic PM fungi for successful host colonization.
There are now six anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) approved for first-line ALK-positive non-small cell lung cancer (NSCLC) therapy, improving survival and quality of life. However, real-world data on treatment outcomes, predictors of discontinuation, and sequencing strategies remain scarce, while direct comparisons between second- and third-generation TKIs are limited. This global longitudinal observational study evaluated patients with ALK-positive NSCLC, with data collected via online surveys from September 2022 to April 2025. Treatment patterns, outcomes, and factors associated with time to discontinuation (TTD) were assessed using descriptive statistics and univariable regression. Overall, 1,111 patients from 71 countries were included (64% female; median age at diagnosis 53 years; 28% with a smoking history). Crizotinib was predominantly the first TKI administered, although prescribing patterns shifted over time (crizotinib before 2016, alectinib between 2017 and 2022, and lorlatinib thereafter). After the follow-up period (median of 20.7 months), 60% of patients remained on their initial TKI, with TTD varying significantly across agents. Factors associated with prolonged TTDs included radiotherapy, prior chemotherapy, delayed therapy initiation, and treatment in India (crizotinib) and retirement, prior chemotherapy, and treatment in the United Kingdom (alectinib). Gastroesophageal reflux disease, thyroid disease, TP53 mutations, and ALK V3a/b fusions were associated with a short TTD. Globally, alectinib to lorlatinib was the most common treatment sequence. Discontinuations because of toxicity were the highest with crizotinib and ceritinib and the lowest with lorlatinib and alectinib. This multinational registry-based analysis highlights evolving global treatment patterns, supports newer TKIs' effectiveness, and identifies clinical and molecular factors associated with treatment duration.
Objectives. To examine telehealth use and modality choice among US older adults (≥ 65 years) and identify factors associated with adoption and modality preference in the postpandemic era. Methods. Using data from 2723 device-owning older adults in the 2024 Health Information National Trends Survey (HINTS 7; nationally representative, March-September 2024), multivariable logistic and multinomial logit models examined associations between telehealth use, modality, and covariates, including socioeconomic factors, health conditions, digital literacy, and prior health information technology use. Results. Overall, 31.4% of older adults used telehealth in 2024 (video: 12.38%; phone-only: 12.41%). Higher odds of use were associated with Hispanic ethnicity (adjusted odds ratio [AOR] = 1.92; 95% confidence interval [CI] = 1.07, 3.81), lung disease (AOR = 2.32; 95% CI = 1.22, 4.42), depression (AOR = 1.89; 95% CI = 1.01, 3.54), and frequent provider visits; lower odds were associated with nonmetropolitan adjacent residence (AOR = 0.36; 95% CI = 0.17, 0.76) and health insurance coverage (AOR = 0.13; 95% CI = 0.03, 0.62). In addition to these factors, video use was uniquely associated with higher income, ability to use apps without assistance, and prior health IT use. Nonusers most commonly cited preference for in-person care (45.7%) or not being offered telehealth (13.4%). Conclusions. Telehealth use has stabilized but remains low among US older adults, with persistent geographic and socioeconomic disparities in modality choice. Policies ensuring audio-only parity and targeted digital literacy interventions are essential to promote equitable telehealth access as telehealth becomes integrated into postpandemic care. (Am J Public Health. 2026;116(S3): S218-S228. https://doi.org/10.2105/AJPH.2026.308575).
Sexually transmitted infections (STIs) remain a major public health issue worldwide, particularly in low- and middle-income countries. Among women, STIs are associated with an elevated risk of HIV infection, infertility, and pelvic inflammatory diseases. This study examined the prevalence of self-reported STIs and related symptoms and their associated factors among women in Ghana. Data from the 2022 Ghana Demographic and Health Survey was used for the study. A weighted sample of 12,997 women of reproductive age (15-49 years) was included in the analysis. Four outcome variables were analysed: (1) any STIs, (2) genital discharge, (3) genital sores or ulcers, and (4) a composite measure of any STIs or genital discharge or genital sores/ulcers (STIs and related symptoms). Multivariable binary logistic regression was used to identify the factors associated with self-reported STIs and related symptoms, with results presented as adjusted odds ratios (aORs) and 95% confidence intervals (CIs). The analysis accounted for sampling weights, clustering, and stratification. All analyses were performed in Stata version 17.0. The prevalence of self-reported any STIs, genital sores or ulcers, and genital discharge among women in Ghana was 6.4% (95% CI: 5.8-7.1), 9.1% (95% CI: 8.3-10.0), and 21.9% (95% CI: 20.6-23.4), respectively. An estimated 26.7% (95% CI: 25.2-28.2) of women reported STIs and related symptoms. Women aged 40-44 (aOR = 0.70, 95% CI: 0.52-0.93) and 45-49 (aOR = 0.55, 95% CI: 0.40-0.76) had lower odds of self-reporting STIs and related symptoms than those aged 15-19. Women who first had sex at age 17 or older (aOR = 0.81, 95% CI: 0.72-0.91) also had lower odds of self-reporting STIs and related symptoms than those who first had sex at age 16 or younger. Additionally, women with one (aOR = 0.73, 95% CI: 0.61-0.87), two (aOR = 0.68, 95% CI: 0.55-0.85), three (aOR = 0.71, 95% CI: 0.56-0.90), and four or more children (aOR = 0.61, 95% CI: 0.48-0.77) had lower odds of self-reporting STIs and related symptoms compared with those without children. Women who were cohabiting (aOR = 0.81, 95% CI: 0.67-0.98) and those previously married (aOR = 0.78, 95% CI: 0.62-0.98) had lower odds of self-reporting STIs and related symptoms than those who had never been in a union. Conversely, women who engaged in multiple sexual partnerships (aOR = 1.95, 95% CI: 1.48-2.58) and those who visited the health facility in the past 12 months (aOR = 1.21, 95% CI: 1.08-1.35) had higher odds of self-reporting STIs and related symptoms compared with those without multiple sexual partnerships and those who did not visit the health facility in the past year, respectively. Compared with women from the Western region, those from Ahafo (aOR = 1.62, 95% CI: 1.28-2.05) and Northern (aOR = 1.82, 95% CI: 1.45-2.28) regions had higher odds of self-reporting STIs and related symptoms. Self-reported STIs and related symptoms are prevalent among women of reproductive age in Ghana, with variations across the regions. Factors associated with self-reported STIs and related symptoms were women's age, parity, age at first sex, marital status, number of sexual partners, and health facility visits. Targeted sexual health education focusing on high-risk sexual behaviours, as well as region-specific interventions, are needed to help prevent the incidence of STIs and related symptoms.
Professional satisfaction among physiotherapists is important for workforce sustainability; however, the role of regional socio-economic context remains insufficiently understood. This study compared professional attitudes, job satisfaction and global professional satisfaction among physiotherapists working in two provinces with different socio-economic development levels and examined factors associated with global professional satisfaction. This cross-sectional study included physiotherapists from Denizli (higher-SEGE province, n = 102) and Mus (lower-SEGE province, n = 53), classified according to the Socio-Economic Development Index (SEGE-2025). Data were collected using the Attitude Scale Toward the Physiotherapy Profession, the Minnesota (Job) Satisfaction Questionnaire Short Form (MSQ), the Job Satisfaction Scale, a single-item global professional satisfaction rating, and a researcher-developed job-related perceptions questionnaire. Physiotherapists in the higher SEGE province reported more positive professional attitudes and higher global professional satisfaction, despite their longer working hours and more working days (p < 0.05). Physiotherapists in the lower-SEGE province reported higher income (p < 0.001), while salary satisfaction responses differed between provinces. Regression analysis identified monthly income (ß = 0.128, p = 0.034), professional attitudes (ß = 0.317, p < 0.001), job satisfaction scale total score (ß = 0.191, p = 0.023), MSQ general satisfaction (ß = 0.319, p < 0.001) and province-level SEGE score (ß = 0.138, p = 0.036) as significant predictors. Findings suggest that physiotherapists' global professional satisfaction is shaped by attitudinal, organizational and structural factors, rather than income alone. Non-financial workforce strategies may be particularly important in lower-SEGE regions.
Injuries are a leading public health priority within adolescent populations; however, few cross-national studies have examined their epidemiology over time. We described time trends in adolescent self-reported medically treated injury across 31 mainly European countries over 20 years, then explored whether observed temporal trends varied according to the prevalence of known behavioral risk factors. The data source included six cycles of the Health Behavior in School-aged Children study (2002-22; weighted n = 954 298, participants aged 11-15 years). Outcomes included self-reports of any and multiple medically treated injuries. Measures of behavioral risks included indicators of violence, substance use, and physical activity. Within countries reporting increases in injuries, variations in reported engagement in known behavioral risk factors were examined. Nearly half of adolescents reported at least one medically treated injury (47%-53% of boys; 38%-44% of girls) and nearly one quarter reported multiple injuries (23%-30% of boys; 16%-22% of girls). In the pooled analysis, temporal trends included increases in any medically treated injury for girls (all age groups) and boys (11 years only) and multiple injuries (boys and girls, all age groups). At the country-level, we observed more temporal increases than decreases. Increases in physical activity were observed coincident with observed injury trends. In one of the largest European analyses of its kind, we demonstrated the ongoing burden of adolescent injury. Persistently high rates of adolescent injuries are concerning, and the origins of temporal increases require an initial focus on sport and physical activity.
Movement behaviour guidelines should be tailored to contextual factors influencing physical activity, sedentary behaviour, and sleep to support effective mobilization. Compared to urban areas, rural communities have distinct environmental characteristics and require context-specific strategies to promote healthy movement behaviours. This study aimed to evaluate awareness and knowledge of the Canadian 24-Hour Movement Guidelines for Adults (18-64 years) living in rural communities and explore how to adapt the Canadian 24-Hour Movement Guidelines Communications Toolkit for greater impact and relevance. We adopted an explanatory sequential mixed methods study design, in which adults living in rural communities of British Columbia, Canada, completed a cross-sectional survey (N = 76) followed by individual interviews (N = 12). Survey data were analysed for awareness and knowledge of Movement Guidelines using descriptive statistics and Chi-squared tests. Interview data were analyzed following a deductive thematic approach using the Behaviour Change Wheel to identify the barriers and facilitators to meeting guideline recommendations. Approximately half of the participants reported being aware of the guidelines (44.7%), 64.5% reported moderate knowledge of recommendations, and 27.6% of participants reported meeting guidelines for physical activity, sedentary behaviour, and sleep. Participants perceived factors associated with physical opportunities and psychological capabilities to have strong influences on their ability to meet movement behaviour guidelines. Recommendations for adapting 24-Hour Movement Guidelines for rural communities include providing additional information on being active outdoors and at home, information on discerning sedentary behaviour and inactivity, and tips to combat seasonal changes in daylight.
With rising incidence of pediatric retina disease, this study aimed to identify geographic and socioeconomic factors that predict residential access to pediatric retinal specialists. This cross-sectional, retrospective study identified pediatric retina specialists in the United States and de-identified census tract-level data from public datasets. An origin-destination cost matrix was used to calculate travel time to the closest pediatric vitreoretinal specialist. Factors associated with greater travel burden to the nearest pediatric retinal specialist included residing in census tracts that were rural (P < .001), in the South vs Northeast (P = .009), low income (P < .0001), and low education (associate and some college vs bachelor's degree; P = .003 and .015). Counties with higher proportion of very low birth weight infants had significantly less travel time (P < .001). Counties with higher incidences of very low birth weight infants experience reduced travel durations to pediatric retina specialists. However, residents in rural, low-income, low-education census tracts, particularly in Southern regions, face greater travel burdens.
To describe the long-term trajectories of cognitive impairment in older adult cancer survivors and to identify factors associated with distinct trajectories. Data were sourced from the National Health and Aging Trends Study (2015-2021), a nationally representative cohort study of community-dwelling older adults aged 65 years or older. Cognitive function was assessed annually with self-reported diagnoses and cognitive function tests. Group-based trajectory models were used to identify cognitive trajectories, and multinomial logistic regression models were used to examine associations between baseline characteristics and trajectory affiliations. 1,564 older adults with cancer and 3,447 without cancer were included. Four trajectories of cognitive impairment were identified: low-stable (64%), low-slowly deteriorating (18%), low-rapidly deteriorating (6%), and persistent-high (12%). Older age, lower education and income levels, poorer self-rated health, physical frailty, and comorbidities were significantly associated with persistent-high or deteriorating trajectories (p < 0.05). The current study highlights the specific dynamic features of cognitive decline among older adult cancer survivors and identifies risk factors for early identification of patients at high risk for less favorable trajectories.
This study investigates how hypoxia remodels the extracellular vesicle (EV) proteome to promote metastasis in breast cancer (BC) cells. EVs from hypoxic MCF-7 and MDA-MB-231 cells were characterized and shown to enhance epithelial-mesenchymal transition (EMT), migration, invasion, and clonogenicity in recipient cells. Quantitative proteomics identified over 1250 EV proteins, with 78 commonly regulated by hypoxia across both cell lines. Pathway analysis revealed hypoxia-induced EV enrichment of ribosomal, chromatin remodeling, mitochondrial, and one-carbon metabolism proteins, alongside depletion of immune-modulatory factors. Interestingly, key one-carbon metabolism enzymes (SMS, CAD, and AHCYL1) were consistently upregulated in hypoxic EVs shed by both the cell lines. Notably, AHCYL1, a regulator of the methylation cycle enzyme AHCY, is significantly upregulated under hypoxic conditions. Our findings demonstrate that hypoxic EVs promote an increase in histone H3K9 trimethylation levels in recipient cells. This epigenetic shift downregulated epithelial and metastasis-suppressor genes (CDH1, EpCAM, and DKK1) while sustaining expression of EMT transcription factors (ZEB1 and SNAIL), thereby stabilizing EMT and enhancing invasiveness. Collectively, we describe a hypoxia-driven EV proteome that links metabolic reprogramming to epigenetic enforcement of metastatic traits in BC.
Stool-based testing is used for non-invasive colorectal cancer screening. The multi-target stool DNA (mt-sDNA) test has higher completion rates than other stool-based tests; however, data are scarce on mt-sDNA test adherence among Veterans Health Administration (VHA) insurance plan enrollees in the United States. We retrospectively assessed adults aged 45 to 75 years prescribed mt-sDNA testing through a VHA insurance plan, including veterans receiving VHA-authorized care and civilians covered by the Civilian Health and Medical Program of the Department of Veterans Affairs (CHAMPVA). Study data were obtained from the Abbott database (August 2022-January 2026). The primary outcome was test completion (adherence) within 365 days of kit shipment. Kaplan-Meier and log-rank analyses were used to evaluate time to adherence, and logistic regression was used to evaluate factors associated with mt-sDNA test adherence. Of 8,613 enrollees prescribed mt-sDNA testing, 72.4% (n = 6,234) were adherent; median time to adherence was 16 days. Metropolitan residence was associated with lower adherence (reference: small town; adjusted odds ratio [OR], 0.78; 95% confidence interval [CI], 0.65-0.92; P = .004). Factors associated with higher adherence included median annual household income ≥$125k (reference: <$50k; OR, 1.49; CI, 1.04-2.12; P = .029), test prescription by an obstetrician/gynecologist (reference: nurse practitioner/physician assistant; OR, 1.45; CI, 1.10-1.92; P = .009), and opting in to email and text notifications (reference: no digital notification; OR, 2.02; CI, 1.65-2.46; P < .001). Time to adherence differed significantly by outreach type and prior mt-sDNA return history (both log-rank P < .0001). Adherence to mt-sDNA testing among VHA enrollees was higher than stool-based test adherence rates previously reported among United States veterans or the general population. These findings support broader integration of mt-sDNA testing within VHA colorectal cancer screening programs to help improve screening participation. Future studies could assess follow-up colonoscopy adherence in an effort to optimize colonoscopy utilization.
Dementia affects millions globally and presents diverse challenges shaped by personal, social and environmental factors. People living in under-served rural, coastal and deprived communities often face additional barriers to diagnosis, care and support, limiting person-centred approaches. These inequalities can negatively impact quality of life, social inclusion and health outcomes. Whilst dementia experiences have been widely studied, the influence of geographical context remains underexplored. Understanding this is essential to improving equitable, person-centred care across diverse settings. MEDLINE, PsycInfo, Cochrane Library and Web of Science were searched from inception in February 2025 for qualitative studies on people's experiences of living with dementia in rural, coastal or deprived areas. The review was not limited by country or date. Data were coded and thematically synthesised using NVivo. Seventy-three full texts were screened using Rayyan and 15 studies were included in the review. Thirteen studies were based in rural areas and two in deprived areas. No included studies were set in coastal areas. Four analytical themes were developed: navigating stigma, privacy and disclosure, navigating fragmented healthcare systems and services, lack of appropriate and accessible services and positive experiences of managing dementia. Key barriers to managing dementia included limited service availability, unsuitable support, stigma and logistical challenges. Findings underscored the need for person-centred, context-sensitive care that considers geographic, social and cultural factors. Future research should further explore diverse under-served settings to inform equitable dementia care particularly in deprived and coastal areas.
Neuropsychological performance is influenced by demographic/premorbid factors in addition to acquired cognitive impairment. This study examined relationships between educational attainment, reading ability, and executive functions in a clinical sample. We conducted a retrospective analysis of 71 adult native English-speaking neuropsychology outpatients who completed Color Trails Test (CTT), Trail Making Test (TMT), Wechsler Test of Adult Reading (WTAR), and Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference, Verbal Fluency, and Design Fluency subtests. Linear regressions and t-tests examined associations among education, WTAR scores, and executive performance. Both TMTB and CTT2 significantly predicted cognitive impairment ratings (CTT2 (B = .008, p < .001) and Trails B (B = .008, p < .001)), and their predictive strength did not differ significantly (z = -.86, p > .05). WTAR scores demonstrated stronger and more consistent associations with executive performance and impairment ratings than years of education. In patients with lower WTAR scores (WTAR≤ 85, N = 19), performance on CTT2 was significantly faster than TMTB (t[18] = -2.726, p = .014), while no significant difference was observed in the higher WTAR group. These preliminary findings from an exploratory retrospective study support further investigation of the influence of reading ability on executive functioning test performance. Future research should examine potential mechanisms, including educational quality, literacy-related factors, and premorbid cognitive ability.
Objectives. To identify factors associated with longitudinal change in multisector collaboration in the delivery of essential public health services in the United States. Methods. We measured correlates of change in the intensity of collaboration in essential public health service delivery using data from the 1998 to 2023 National Longitudinal Survey of Public Health Systems. We used paired t tests to examine changes in collaboration intensity across sectors. We then estimated 2-part models to identify correlates of change in collaboration probability and intensity. Results. Multisector collaborations did not change significantly between 1998 and 2023. Rural jurisdictions were least likely to have expanded their multisector collaborations across this time period, and they did so at a lesser magnitude. Decentralized local public health department governance was associated with an increase in multisector collaboration but only among urban jurisdictions. Conclusions. Urban jurisdictions showed greater multisector collaboration expansion between 1998 and 2023 than their rural counterparts. Rural jurisdictions may face unique challenges to partnership building and collaboration, and these challenges may be exacerbated under decentralized governance structures. (Am J Public Health. 2026;116(S3): S192-S201. https://doi.org/10.2105/AJPH.2026.308536).
Late cytopenia (beyond day+30 post-CAR T-cell) is a significant complication following CD19-directed chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). However, available data remain limited and heterogeneous. In this retrospective multicenter study, we evaluated the incidence, patterns, risk factors, and impact of late cytopenia in patients treated with CD19 CAR T-cells. A total of 444 patients with R/R LBCL at eight academic centers within the Cell Therapy Consortium between April 2016 and May 2023 were included. After excluding patients with events (relapse, new treatment, death) or lost to follow-up, grade ≥3 cytopenias were observed in 47%, 34%, 19%, 21%, and 11% of patients with available data at 1, 2, 3, 6, and 12 months post-infusion. Among 307 patients with complete hematologic data, neutropenia consistent with late immune effector cell-associated hematotoxicity was identified in 103 patients (33.6%) between days 30 and 100. Multivariable analysis identified a high CAR-HAEMATOTOX score (≥2) as a predictor of cytopenia at 3 months whereas receipt of bridging systemic chemotherapy and axicabtagene ciloleucel was associated with cytopenia at 6 months post-CAR T-cell. The presence of late cytopenia was associated with a higher 1-year non-relapse mortality (11% vs 4.4%, P=0.038), worse 2-year progression-free survival (38% vs 67%, P=0.035) and worse 2-year overall survival (60% vs 76%, P=0.016). In conclusion, late cytopenia is a common and clinically meaningful toxicity after CD19 CAR T-cell therapy. Recognition of risk factors and consistent monitoring are essential for optimizing post-CAR T-cell care and reducing treatment-related mortality.
Despite extensive investigation, the molecular control of developmental hemoglobin expression remains incompletely elucidated. Hemoglobin switching is controlled by transcription factors, miRNAs, and RNA-binding proteins (RBPs) that enforce gene regulatory changes through development. Here we examine the role of the heterochronically silenced N6 methyladenosine (m6A) RNA-binding protein IGF2BP1 that was previously described to regulate HBG1/2 indirectly by suppressing BCL11A expression through an unknown mechanism. We find that IGF2BP1 binds and activates HIC2, itself a BCL11A repressor. Furthermore, we identify that IGF2BP1 plays a BCL11A-independent role by direct binding to HBG1/2 to promote its translation. Stop codon-proximal m6A-modified coding sequences within HBG2 transcripts are necessary and sufficient for direct positive regulation mediated by IGF2BP1. This work deepens the mechanistic understanding of hemoglobin switching and suggests a physical relationship between heterochronic RBPs and globin transcripts.